Therapeutic Inhibition of MIF in Rheumatoid Arthritis

Award Information
Agency: Department of Health and Human Services
Branch: N/A
Contract: 2R44AR056908-02A1
Agency Tracking Number: R44AR056908
Amount: $988,799.00
Phase: Phase II
Program: SBIR
Awards Year: 2012
Solicitation Year: 2012
Solicitation Topic Code: NIAMS
Solicitation Number: PA11-096
Small Business Information
BOX 8175, NEW HAVEN, CT, -
DUNS: 142406110
HUBZone Owned: N
Woman Owned: N
Socially and Economically Disadvantaged: N
Principal Investigator
 (203) 503-0383
Business Contact
Phone: (203) 393-9439
Research Institution
DESCRIPTION (provided by applicant): The long-term product goal of this project is a small molecule therapeutic to treat rheumatoid arthritis (RA), which acts by reducing the inflammatory response triggered by the pro-inflammatory cytokine macrophage migration inhibitory factor (MIF). Since MIF is an upstream regulator of the inflammatory cascade, small molecule therapeutics targeting MIF activity are expected to provide effective treatment for RA, which currently afflicts 4 million people in the US alone and for which there is no curative therapy. To this end, in Phase I of this SBIR project, we screened 200,000 compounds for MIF inhibitors and identified a number of small molecules that block MIF-driven cellular activation pathways that are associated withthe immunopathology of RA. For this proposal we selected two inhibitors that are structurally unique and possess functional groups that have not been previously associated with MIF inhibitory activity. They appear to interact with MIF by distinct mechanisms, and they are not cytotoxic to mammalian cells. In the continuation of this project, we propose to elucidate their precise mechanisms of action by obtaining MIF-inhibitor co-crystal structures. Further, using medicinal chemistry guided by structural data, we propose to obtain structure-activity relationships and modify the compounds to improve their MIF-inhibitory activities in an effort to obtain molecules that are efficacious in the RA mouse model. All of these efforts are expected to yield a lead compound suitable for further development towards a small molecule therapeutic for RA. PUBLIC HEALTH RELEVANCE: The goal of this project is to advance a promising small molecule compound towards development into a new drug for the treatment of rheumatoidarthritis (RA), a disease that afflicts up to 4 million people in the US. This compound appears to inhibit the inflammatory component of RA that is caused by the cytokine macrophage migration inhibitory factor (MIF). Since MIF acts upstream in the inflammatory cascade in RA, inhibition of this activity will address many of the downstream effector pathways that are ultimately responsible for joint destruction.

* Information listed above is at the time of submission. *

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